PROJECT SUMMARY Alzheimer's disease and related dementias (ADRD) are highly debilitating disorders that currently affect over 5 million Americans, and the prevalence is expected to rise rapidly as the population ages. The causes of ADRD remain poorly understood, and there is a critical need to identify novel modifiable risk factors as well as biological mechanisms of ADRD. Recent epidemiological studies, including those published by investigators of the proposed study, suggest that age-related impairment of the internal circadian clock may play a role in the development of ADRD in older men and women. However it remains unclear what biological mechanisms may drive the associations between weakened circadian rhythms and ADRD. Recent applications of metabolomics in epidemiological and clinical studies suggest that there may be common metabolic pathways associated with both circadian disruption and ADRD. This raises the possibility that age-related impairment in circadian rhythms may drive metabolic changes, which in turn lead to the development of ADRD. This hypothesis is further supported by our exciting metabolomics data from 50 men in the Osteoporotic Fractures in Men (MrOS) study: We found that both weakened rest-activity rhythms and impaired cognitive function are associated with increases in gamma-glutamyl dipeptides, bile acids, and acylcarnitines, but decreases in polyunsaturated fatty acids. Based on the compelling data from epidemiological studies, as well as the intriguing findings from our metabolomics pilot, we propose to comprehensively examine characteristics of the rest-activity rhythms and metabolomic profiles in relation to long-term cognitive outcomes. Our metabolomics study will include 1500 older men and women with 500 incident dementia cases from two unique and complimentary cohorts, the Women's Health Initiative and the Osteoporotic Fractures in Men studies. The current study includes three specific aims and one exploratory aim: Aim 1: Determine the gender-specific relationships between rest- activity rhythms and long-term cognitive outcomes including ADRD in older men and women. Aim 2: Identify metabolomics signatures that are associated with characteristics of rest-activity rhythms and incident ADRD, respectively. Aim 3: Test whether common metabolites and pathways mediate relationships between rest- activity rhythms and incident ADRD. For the Exploratory Aim, we will examine the relationship between baseline rest-activity rhythms, changes in metabolomics markers, and long-term cognitive outcomes in the subset of 300 MrOS participants with repeated serum samples. Our study is innovative because it focuses on weakened circadian rhythms as a novel risk factor for ADRD. Moreover, it goes beyond characterizing associations and focuses on identifying metabolic pathways linking rest-activity rhythms with ADRD in a large population of free-living older adults. The proposed study is significant because it has the potential to identify predictive and mechanistic biomarkers that may lead to better prevention, diagnosis and treatment of ADRD.